Abstract 415A: Regulation of NCAPG by miR-99a-3p (passenger strand) inhibits cancer cell aggressiveness and is involved in CRPC

Abstract

Abstract In developed countries, prostate cancer (PCa) is one of the most commonly diagnosed cancers, identified by prostate-specific antigen (PSA) screening; PCa is also the third leading cause of cancer-related death among men. Most naïve PCa initially responds well to androgen-deprivation therapy (ADT). However, during ADT treatment, PCa cells acquire ADT treatment resistance and progress to a lethal pathology known as castration-resistant prostate cancer (CRPC). Cancer cells that have reached CRPC can cause distant metastasis, and effective treatments for patients with CRPC have not yet been established. Identification of the molecular pathogenesis underlying acquisition of androgen-independent and metastatic signaling pathways based on advanced genomic approaches is essential for further understanding of this disease.MicroRNAs (miRNAs) are endogenous small RNA (molecules 18-23 bases in length) that act as central players regulating the expression control of protein-coding and protein-noncoding RNAs. Interestingly, a single miRNA can directly regulate a vast number of RNAs in human cells. Therefore, aberrant expression of miRNAs can disrupt normal control of RNA expression in cancer cells. Furthermore, dysregulation of miRNAs is contributed to cancer cell malignancies, such as progression, metastasis, and treatment resistance. Analyses of RNA-sequencing of microRNA (miRNA) expression revealed that miR-99a-3p (passenger strand) is significantly downregulated in several types of cancers. In this study, we aimed to identify novel miR-99a-3p regulatory networks and therapeutic targets for CRPC. The expression levels of miR-99a-3p was significantly lower in PCa and CRPC tissues than in normal tissues (P = 0.0047 and P = 0.0001). Ectopic expression of miR-99a-3p significantly inhibited cancer cell proliferation, migration, and invasion in PCa cells (P < 0.0001). Non-SMC condensin I complex subunit G (NCAPG) was a direct target of miR-99a-3p in PCa cells. Overexpression of NCAPG was detected in CRPC clinical specimens and TCGA data showed that high NCAPG expression was significantly associated with shorter disease-free survival (P = 0.0009) and advanced clinical stage in PCa. Knockdown of NCAPG markedly inhibited cancer cell proliferation, migration, and invasion (P < 0.0001). Moreover, the proliferation, migration, and invasion abilities were recovered by cotransfection with NCAPG and miR-99a-3p. These results indicated that NCAPG affected the aggressiveness in PCa. The passenger strand miR-99a-3p acted as an antitumor miRNA in naïve PCa and CRPC. NCAPG was regulated by miR-99a-3p, and its overexpression was involved in CRPC pathogenesis. Involvement of passenger strand of miRNA in cancer pathogenesis is novel concept and identification of antitumor miRNA regulatory networks in CRPC might be provided novel prognostic markers and therapeutic targets for this disease. Citation Format: Takayuki Arai, Atsushi Okato, Yasutaka Yamada, Sho Sugawara, Akira Kurozumi, Satoko Kojima, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki. Regulation of NCAPG by miR-99a-3p (passenger strand) inhibits cancer cell aggressiveness and is involved in CRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 415A.